Epilepsy is a complex CNS condition involving excessive neuronal discharges that result in the occurrence of seizures (Stefan H, Feuerstein T J, Pharmacol Therapeut 2007; 113:165-83).
Seizures may be localized (focal) or generalized within the brain. (Smith M, Wilcox K S, White H S, Neurotherapeutics 2007; 4:12-17)
Seizures may be expressed outwardly as convulsions or they may be non-convulsive (Kwan P, Brodie M J, Expert Opinion on Emerging Drugs 2007; 12:407-22). Focal (partial) seizures are the most common in humans.
Epilepsy occurs in approximately 0.5 to 1% of the human population (Smith M, Wilcox K S, White H S, Neurotherapeutics 2007; 4:12-17). Chronic, daily treatment with antiepileptic drugs (AEDs) continues to be the standard of care for these patients.
These existing AEDs, however, have varying degrees of effectiveness in suppressing seizures in humans (Stefan H, Feuerstein T J, Pharmacol Therapeut 2007; 113:165-83).
In particular, it is estimated that 30% of all epilepsy patients are refractory to current AEDs (Malawska B, Kulig K, Expert Opin Inv Drug 2008; 17:361-69).
Epilepsy patients who are refractory, do not respond to the currently available AEDs (Hitiris N, Brodie M J, Curr Opin Neurol 2006; 19:175-80).
Refractory epilepsy is defined as failure of adequate trials of two tolerated and appropriately chosen and used AED (anti-epilepsy drug) schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom (Kwan P, Arzimanoglou A, Berg A T, et al. (vol 51, pg 1069, 2010). Epilepsia 2010; 51:1922).
Although suboptimal, therapeutic strategies for refractory patients frequently include polytherapy and drug rotation performed on a trial-and-error fashion which usually has limited success (Pathan S A, Jain G K, Akhter S, Vohora D, Ahmad F J, Khar R K, Drug Discovery Today 2010; 15:717-32). The percentage of epilepsy patients that remain refractory to available drugs has not improved appreciably over the decades.
Treatment of seizures with anticonvulsant drugs also has drawbacks due to the significant occurrence of side-effects. Common side effects of AEDs include sedation, somnolence, depression and other neuropsychological deficits (Wuttke T V, Lerche H, Expert Opinion on Investigational Drugs 2006; 15:1167-77) that interfere with a patient's quality and functioning in daily life. Side effects also are a major limitation to escalating patient doses in attempts to suppress seizures.
As described above, there is a significant need for new anticonvulsant drugs that are more efficacious and have lesser side effects than the currently available compounds. As a group antiseizure compounds are known to interact with a diversity of molecular targets that suppress nerve excitability and likely do so by exerting multiple mechanisms of action. Known mechanisms include effects on voltage-gated ion channels, non-specific cation channels, ligand-gated ion channels, excitatory amino acid receptors, neurotransmitter transporters, and neurotransmitters.
The alkyl substituted phenol, propofol, has good anticonvulsant activity in human status epilepticus (Kinirons P, Doherty C P, Eur J Emerg Med 2008; 15:187-95) the most debilitating form of human seizures.
Unfortunately, propofol cannot be used for more widespread and chronic/daily use. (Marik P E, Varon J, Chest 2004; 126:582-91).
Although approved for anesthesia, it is only used in acute care settings due to sedation and respiratory depression side-effects (Langley M S, Heel R C, Drugs 1988; 35:334-72).
The mechanisms by which propofol inhibits human status epilepticus are unknown. It is believed that propofol's anesthetic/sedative effects result from it being an agonist and potentiator of the GABAA receptors (Bali M, Akabas M H, Mol Pharmacol 2004; 65:68-76)
The mode of action of propofol analogs is similarly elusive (Krasowski M D, Jenkins A, Flood P, Kung A Y, Hopfinger A J, Harrison N L, Journal of Pharmacology and Experimental Therapeutics 2001; 297:338-51).
GABAA receptor agonism/potentiation is also known to be a mechanism of some anticonvulsant compounds (Myhrer T, Nguyen N H T, Enger S, Aas P, Arch Toxicol 2006; 80:502-07).
GABAA receptor agonism/potentiation is presumed to be a component of propofol's anticonvulsant mechanism (Ragavendran J V, Sriram D, Kotapati S, Stables J, Yogeeswari P, European Journal of Medicinal Chemistry 2008; 43:2650-55).
GABAA receptor stimulation depresses nerve conduction by hyperpolarizing the neuronal membrane and suppressing impulse conduction. GABA receptors, which exist as multiple isoforms with different sensitivities to agonists (Atack J R, Curr Top Med Chem 2011; 11:1176-202).
GABA receptors are known to be present in nerves that excessively fire causing seizures. Other studies show that propofol can block sodium channels (Jones P J, Wang Y S, Smith M D, et al., J Pharmacol Exp Ther 2007; 320:828-36).
Propofol has also been reported to down-regulate glutamatergic synaptic transmission (Snyder G L, Galdi S, Hendrick J P, Hemmings H C, Neuropharmacology 2007; 53:619-30), other known anticonvulsant mechanisms. Unlike the barbiturate or benzodiazepine drug families, which have different members useful for anesthesia/sedation and anticonvulsant activity, propofol is the sole member of the alkyl phenolic class on the market.
Previously it has been shown that carvacrol, thymol, and other substituted phenols in essential oils have antibacterial and antifungal properties and cause. (Stefanakis et al. (2013) Food Control 34:539-46).
Certain substituted phenols show bacteriostatic and bacteriocidal effects toward Eschericia coli, Staphylococcus aureus, Listeria monocytogenes, and Bacillus cereus (Klein et al. (2013) Current Microbiology 67: 200-08).